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[19441 Synthetic Analgesics. Part I I . 265

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69. Synthetic Analgesics. Part I I . A New Xynthesis of Pethidine and Ximilar

Compounds. *
9

By F. BERGEL,A. L. MORRISON,
and H. RINDERKNECHT.
A new method of synthesising 4-arylpiperidine-4-nitriles is described. Arylacetonitriles were condensed
with 2 mols. of p-chloroethyl vinyl ether, and the resulting aa-bis- (fY-vinyloxyethy1)arylacetonitrileshydrolysed
t o the corresponding di-alcohols, which were chlorinated and then treated with primary amines to give the
above nitriles. The same di-alcohols were obtained by hydrolysis of act-bis-(p-alkoxymethyloxyethy1)aryl-
acetonitriles, which were prepared by condensation of arylacetonitriles with 2 mols. of alkyl-/3-chloroethyl-
formals.
In this way, 4-phenyl-1-methylpiperidine-4-nitrile and 4-o-toZyZ-l-methyZp~per~d~ne-4-nitrilewere prepared.
Hydrolysis with concentrated hydrochloric acid gave the corresponding carboxylic acids. Several esters of
4-phenyl-1-methylpiperidine-4-carboxylicacid have been prepared. The ethyl ester was also obtained by
direct alcoholysis of the nitrile.

CONDENSATION of phenylacetonitrile with alkyl halides and alkylene dihalides, in the latter case to give phenyl-
cydoparaffin nitriles, in presence of sodamide was described by Bodroux and Taboury (Compt. rend., 1910,
150, 1241, etc.) and Case ( J . Amer. Chem. Soc., 1934, 56, 715). Eisleb later (Bey., 1941, 75, 1435) reported the
synthesis of heterocyclic compounds by the condensation of phenylacetonitriles with P p-dihalogenoethyl-
alkylamines, ethers, and sulphides. In view of the pronounced vesicant nature of PP-dihalogenoethylmethyl-
amine, we looked for another method of preparing 4-arylpiperidine-4-nitriles, which are intermediates of
important analgesics. One of the alternative methods considered was the preparation of ctcc-bis-(p-halogFno-
ethyl)arylacetonitriles which, on condensation with primary amines, would give the desired piperidine nitriles.
Attempts to prepare such dihalogeno-compounds by condensation of phenylacetonitriles with 2 mols. of
chlorobromoethane were unsuccessful, cyclopropane derivatives being the main products. Although ethylene
chlorohydrin may be condensed with the sodio-derivative of phenylacetonitrile (Knowles and Cloke, J . A mer.
Chem. Soc., 1932, 54, 2028), the introduction of a second hydroxyethyl group was found to be impossible.
The use of p-halogenoethyl alkyl ethers gave products which could not be converted into the desired @halogeno-
nitriles, as the agent used for fission of the ether linkage also hydrolysed the nitrile group to the carboxylic
acid, the resulting product being a derivative of a-phenylbutyrolactone, which was of no use for the projected syn-
theses. We finally achieved our aim by condensation of phenylacetonitrile in presence of sodamide with 2 mols.
of P-chloroethylvinyl ether (I)to give aa-bis-( P-vinyZoxyethyl)phenyZaceto~itriZe(11),which on mild acid hydrolysis
yielded aa-bis-(P-hydroxyethyl)~he~yZacetonitr~Ze (111) (cf. Cretcher, Koch, and Pittenger, ibid., 1925, 47, 3083).
The same dialcohol was also obtained by mild acid hydrolysis of aa-bis-(P-methoxymethyZoxyethyl)~henyZ-
acetonitrile (IIa; R = Me), formed by condensation of phenylacetonitrile with 2 mols. of wethyl-P-chloro-
ethylformal ( I a ; R = Me) in presence of sodamide. This di-alcohol on treatment with thionyl chloride in
presence of diethylaniline yielded aa-bis- (p-chZoroethyZ)pkenyZacetonitriZe (IV), which, when condensed with
primary amines such as methylamine or benzylamine in aqueous-alcoholic solution, gave 1-alkyl- or 1-aralkyl-
4-phenylpiperidine-4-nitriles (V). 4-Phenyl- 1-methylpiperidine-4-nitrile thus prepared possessed all the
properties described by Eisleb (loc. cit.) .
The above P-chloroethylalkylformals were more readily prepared by the action of ethylene oxide on chloro-
methyl ethers a t low temperature (cf. Blanchard, Bull. SOC.chim., 1936, 39, 1263) than by the methods
suggested in the literature (Henry, Ber., 1895, 28, Ref. 851).
The hydrolysis of 4-phenyl-1-methylpiperidine-4-nitrile to the corresponding carboxylic acid was easily
achieved by boiling with concentrated hydrochloric acid. I n addition to the ethyl ester (pethidine) and those
esters mentioned by Schaumann (Arch. Path. Ex?. Pharm., 1940, 196, log), we have prepared the n-propyl,
* Cf. B.PP. 550,963 (1943), 550,970 (1943), and 556,976 (1943).
 266 Synthetic Analgesics. Part I I . View Article Online

isopropyl, F-hydroxyethyl, cyclohexyl and allyl esters of 4-phenyl-1-methylpiperidine-4-carboxylicacid. The

ethyl ester was also obtained directly from the nitrile by heating it with an appropriate mixture of alcohol,
sulphuric acid, and water under pressure.
I t I
+H,CN I
I
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\/'

(I.) CI.CH,*CH,*OCH:CH, ROCH ,-O-CH,;cH,c~ (1a.1

-
1
,CH,*CH',*O*CH:CH,

(111.) (IV.1 (V.)

We also synthesised 4-o-tolyl-l-methylpiperidine-4-nitde,the corresponding carboxylic acid, and its ethyl
ester, according t o the above method.
The results of pharmacological tests of the above compounds, obtained in association with Professor A. D.
Macdonald and Dr. G. Woolfe, University of Manchester (Department of Pharmacology) , will be published
elsewhere.
EXPERIMENTAL.
Methyl-B-chloroethylformal (Ia; R = CH,).-Chloromethyl methyl ether (80 g.) was added slowly with stirring te mer-
curic chloride (0-6g.) in dry liquid ethylene oxide (44g.), the temperature being maintained at - 10' by external cooling.
After standing a t room temperature overnight, the colourless product was washed with dilute sodium carbonate solution
and water, dried over anhydrous potassium carbonate, and distilled. The formal was a colourless liquid, b. p. 134-
139" (Found : C1, 25.2. C4H,0,Cl requires C1, 28.504); yield 78-5g. It may be obtained pure by washing repeatedly
with water (Found : C1, 28-8y0),but can be employed in the impure state for condensation with phenylacetonitrile.
B-ChZoroethyZethylforaZ (Ia; R = Et), prepared in a similar manner (yield, 72%), was a colourless liquid, b. p.
62-65'/50 mm. (Found : C1, 20.7. C,H,,O,Cl requires C1, 254%).
aa-Bis- (B'-vinyZoxyethyZ)phenyZacetonitrile (11).-Phenylacetonitrile (431 g.) was added gradually with mechanical
stirring t o a suspension of powdered sodamide (317g.) in a mixture of chloroethyl vinyl ether (867g.) and dry benzene
(4400c.c.). The temperature of the reaction mixture was kept between 40" and 50" until all the nitrile had been added ;
it was then slowly raised t o boiling point, and'refluxing continued for 1 hour. The resulting product was poured into a
large separating funnel and washed twice with water. The benzene was then distilled off, and the residue distilled in a
high vacuum. The n i t d e (7308.) distilled a t 125-135"/0-15 mm. as a colourless oil (Found : C, 73.9, 75-8; H, 7.4,
7.6; N, 6.4,-6.6. Cl,H1,O,N requires C, 74.7; H, 7.4; N, 5.4%). It was difficult ts effect complete separation from
a-(/3'-vinyloxyethyl)phenylacetonitrile, b. p. 1 10/0-15mm., formed as a by-product.
aa-Bis- (/3'-methoxymelhoxyethyZ)~~enyZucet~~t~iZe (IIa; R = CH,) , prepared by condensation of phenylacetonitrile
with B-chloroethylmethylformal (Ia) in a similar manner, was obtained as a faintly yellow oil, b. p. 147-155"/0~05-
0.1 mm. (Found : C, 66-0; H, 7.8; N, 4.9. Cl,H,,04N requires C, 65.6 ; H, 7.8; N,4-8) ; yield 61 yo. The /3'-ethoxy-
homologue was obtained in an analogous manner from phenylacetonitrile and j5-chloroethylethylformal as a slightly
yellow oil, b. p. 167-169"/0+05 mm. ; yield 77%.
JzenyZacetonitriZe, (I11).-(A) aa-Bis- (fY-vinyloxyethyl)phenylacetonitrile (7.9 g.) was SUS-
aa-sis-f/3'-~zydroxyethyZ)p
pended in water (60 c.c.) and heated t o 80" with vigorous stirring. Concentrated hydrochloric acid (2 c.c.) was then
added, whereupon hydrolysis set in with evolution of acetaldehyde. After 10 minutes' stirring, on completion of the re-
action, the mixture was cooled, and the aqueous layer separated from the oil. The oil soon solidified, and was re-
crystallised from ethyl acetate, chloroform, or water, the di-alcohol being obtained as a white crystalline powder. A further
small quantity crystallised .out from the aqueous part on cooling to Oo. Yield of crystalline material, 4.4 g. ; m. p.
96-98' (Found : C, 70.3; H, 7.4; N, 6.7. C,,H,,O,N requires C, 70-3;H, 7-3;N,6.8%)
(B)aa-Bis-(/3'-ethoxymethoxyethyl)phenylacetonitrile(13 g.) was suspended in water (260 c.c.) and heated to 92O,
cancentrated hydrochloric acid (5-2 c.c.) then being added. Formaldehyde and ethyl alcohol were evolved. The mixture
was kept a t 90-92" for 20-25 minutes to complete hydrolysis. After cooling, the di-alcohol was extracted with ethyl
acetate, from which it crystallised after evaporation of some solvent (yield 5.9 g.). It had m. p. 96-98' alone and when
mixed with the product obtained in (A).
aa-Bis-(S'-chZoroethyZ)phenyZacetonit~iZe(IV).-aa-Bis- (p'-hydroxyethyl) phenylacetonitrile (6-0g.) was suspended in
diethylaniline (12-0g.), and thionyl chloride (12.0 g.) added dropwise with efficient stirring and cooling. The mixture
was then warmed to 80" for 30 minutes, cooled t o 40,and poured into a mixture of ice water and ether with vigorous
stirring. The ethereal layer was separated, washed with cold sodium hydroxide solution and water, dried over anhydrous
sodium sulphate, and evaporated. The product distilled a t 135-138"/0~1-0~2mm. as a yellow oil (6.6g.) which solid-
ified on standing; m. p. 52". The n i t d e (IV)may also be purified by recrystallising from alcohol (Found : C, 59.8;
H, 5.4; N, 5.8; C1, 29.0. C1,H1,NCl, requires C, 5Q.5; H, 5.7; N, 5.6; C1, 28.8%).
4-Phenyl-l-methylpiperidine-4-nitriZe(V).-A mixture of aa-bis- (p'-chloroethy1)phenylacetonitrile (5.0 g.), alcohol
(10 c.c.), and a 50% aqueous solution of methylamine (5.1 g.) was heated in a sealed tube at 145" for 17 hours. After
cooling, the solvents were distilled off under reduced pressure, and the residue taken up in dilute hydrochloric acid.
Non-basic material was removed by extraction with ether, the aqueous part made alkaline, and the liberated base
extracted with ether. The extract was washed with water, dried over anhydrous sodium sulphate, and evaporated.
The product distilled a t 126'/0.5 mm. as a faintly yellow oil (3.4g.), which solidified on standing, m. p. 53". Its picrate
 [19441 Synthetic Analgesics. Part I I I . View Article Online
267
melted a t 239-240" after recrystallisation from alcohol and gave no depression in m. p. when mixed with a sample
obtained by Eisleb's method (Zoc. cit.) (Found : C, 53.5; H, 4-5; N, 15.9. Calc. for ClgHlgO,N, : C, 53.2; H, 4.4;
N, 16.3%).
Ethyl 4-PhenyZ-l-nzethyZpiperidine-4-carboxyZate.-A mixture of 4-phenyl-1-methylpiperidine-4-nitrile(20 g.), con-
centrated sulphuric acid (30g., 98%). water (0.26 g.), ethanol (46g.), and ammonium chloride (5-36 g.) was heated in an
autoclave a t 160" for 7 hours, then made alkaline with cold sodium hydroxide solution, and extracted with ether. After
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being washed and dried over anhydrous sodium sulphate, the extract was evaporated. The product distilled at
115"/0.2 mm. as a colourless oil (11.1 g.) and was identical with ethyl 4-phenyl-l-methylpiperidine-Ccarboxylate
obtained by successive hydrolysis of the nitrile and esterification of the acid. From the alkaline mother-liquor, 4-phenyl-
1-methylpiperidine-4-carboxylicacid (6.5 g.) was recovered. n-Propyl 4-phenyl-l-methyl~i~eridine-4-ca~boxyZate hydro-
chloride was prepared from the corresponding acid chloride hydrochloride and n-propyl alcohol according t o Eisleb
(Zoc. cit.) ; m. p. 181-183" (Found : C1, 11.9. Cl,Hz40,NCl requires C1, 11.8%). The isopropyl hydrochloride had m. p.
192-195" (Found : C1, 12.1. C,,H,,O,NCl requires C1, ll-8y0),and the /3-hydroxyethyZ hydrochloride m. p. 195-200
(Found : C1, 11.6. C,,H,,O,NCl requires C1, 12.0y0).
The aZZyZester hydrochloride had m. p. 155-158" (Found : N, 4.5; C1, 11.3. C,,H,,O,NCl requires N, 4-8;C1, 11.9%)
[in the preparation of the free ester a mixture of allyl alcohol and pyridine (2mols.) was added to the acid chloride hydro-
chloride in order to prevent addition of hydrogen chloride to the double bond of the allyl group] ; and the cyclohexyl
hydrochloride had m. p. 23G-236' (Found : C, 67-4;H, 8 . 5 ; N, 4.4; C1, 10.7. C,,H,80,NCl requires C, 67.6; H,8.3;
N, 4.2 ; C1, 10.4y0). The five foregoing hydrochlorides were recrystallised from alcohol-ether.
aa-Bis- (p-vinyloxyethyl)-0-tolyZacetonitriZe.-Powdered sodamide (10 9.) was added in several portions t o a solution
of o-tolylacetonitrile (11 g.) and p-chloroethyl vinyl ether (39g.) in dry toluene (80 c.c.), the temperature of the reaction
mixture being maintained a t about 40". The reaction was completed by refluxing for 2 hours ; the cooled reaction mixture
was then poured into water, the toluene layer separated, washed with water, and evaporated under reduced pressure.
The residue on distillation gave the nitrile as a yellowish oil, b. p. 135--140"/0~1mm. (Found : N, 4.9. C,,H2,02N
requires N, 4.9%).
aa-Bis- (/3'-hydroxyethyZ)-o-toZyZucetonitr~Ze.-The foregoing nitrile was hydrolysed with dilute hydrochloric acid accord-
ing to the method given above, the tem$erature being kept at 90". On cooling, the di-alcohol crystallised in white needles ;
recrystallised from benzene, it had m. p. 95-100" (Found : C, 71-3;H, 7.8. Cl3HI7O2Nrequires C, 71-3;H, 7.8%).
4-(o-ToZyZ)-l-~et~yZpi~eridine-4-nitriZe.--aa-Bis-(~-hydroxyethyl)-o-tolylacetonitrilewas treated with thionyl
chloride as described above, and the crude dichloride used directly for the condensation with methylamine. Crude
dichloride ( 5 g.) was heated with 33% aqueous solution of methylamine (11c.c.) and alcohol (27 c.c.) in a sealed tube at
12@-140" for 8 hours. The solvents were then removed under reduced pressure, and the residue taken up in B~-hydro-
chloric acid (12-5c.c.). On cooling, 4-(o-tolyl)-l-methylpiperidine-4-nitrile hydrochloride (4.0 g.) crystallised ; m. p.
279-280". The picrate had m. p. 265" (decomp.) (Found.: C, 54.9; H, 5.3; N, 16.0. C,,H,,O,N, requires C, 54.3;
H, 4.8; N, 158%).
Ethyl 4-(o-ToZyZ)-1-nzethyZpiperidine-4-carboxyZute.-The corresponding piperidine nitrile hydrochloride (4 g.) was
heated a t 130"with concentrated hydrochloric acid (16c.c.) in a sealed tube for 5 hours. The reaction mixture was made
alkaline with 4~-sodiumhydroxide solution, and carbon dioxide passed through ; the piperidine carboxylic acid (3 9,)
was precipitated in white needles, m. p. 300-310" (decomp.). It was filtered off, dried over phosphoric oxide, and
treated with thionyl chloride (8 c.c.). After refluxing for 15 minutes, the excess thionyl chloride-was removed, and after
addition of ethyl alcohol (8.6c.c.) to the residue, the mixture was heated on the water-bath for 15 minutes and then
filtered fro'm insoluble material. After removal of solvent, the residual oil was distilled, to give the ethyl ester, b. p.
175'/11 mm., as a colourless oil (2.9g.) (Found : C, 73.2 ; H, 8.6; N, 5.9. C,,H,,O,NrequiresC, 73.6 ; H, 8.8; N, 5.5%).
The hydriodzde, a white crystallihe solid, had m. p. 175-176' (Found : I, 32.6. C,sH2402NIrequires I, 32.6%).
RESEARCH LTD., WELWYNGARDENCITY.
ROCHEPRODUCTS
DEPARTMENT, [Received, January 5th, 1944.1